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Structural and functional analysis of the newt lymphatic system.

ABSTRACT: Regeneration competent vertebrates such as newts and salamanders possess a weakened adaptive immune system characterized by multiple connections between the lymphatic system and the blood vascular system called lymphatic hearts. The role of lymphatic vasculature and these lymphaticovenous connections in regeneration is unknown. We used in-vivo near-infrared lymphangiography, ultra-high frequency ultrasonography, micro-CT lymphangiography, and histological serial section 3-dimentional computer reconstruction to evaluate the lymphatic territories of Cynops pyrrhogaster. We used our model and supermicrosurgery to show that lymphatic hearts are not essential for lymphatic circulation and limb regeneration. Instead, newts possess a novel intraosseous network of lymphatics inside the bone expressing VEGFR-3, LYVE-1 and CD-31. However, we were unable to show Prox-1 expression by these vessels. We demonstrate that adult newt bone marrow functions as both a lymphatic drainage organ and fat reservoir. This study reveals the fundamental anatomical differences between the immune system of urodeles and mammals and provides a model for investigating lymphatics and regeneration.

SUBMITTER: Banda CH

PROVIDER: S-EPMC10140069 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Structural and functional analysis of the newt lymphatic system.

Banda Chihena H CH Shiraishi Makoto M Mitsui Kohei K Okada Yoshimoto Y Danno Kanako K Ishiura Ryohei R Maemura Kaho K Chiba Chikafumi C Mizoguchi Akira A Imanaka-Yoshida Kyoko K Maruyama Kazuaki K Narushima Mitsunaga M

Scientific reports 20230427 1

Regeneration competent vertebrates such as newts and salamanders possess a weakened adaptive immune system characterized by multiple connections between the lymphatic system and the blood vascular system called lymphatic hearts. The role of lymphatic vasculature and these lymphaticovenous connections in regeneration is unknown. We used in-vivo near-infrared lymphangiography, ultra-high frequency ultrasonography, micro-CT lymphangiography, and histological serial section 3-dimentional computer re ...[more]

PMID: 37106059

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Project description:Lymphatic structure and function play a critical role in fluid transport, antigen delivery, and immune homeostasis. A dysfunctional lymphatic system is associated with chronic low-grade inflammation of peripheral tissues, poor immune responses, and recurrent infections, which are also hallmarks of aging pathology. Previous studies have shown that aging impairs lymphatic structure and function in a variety of organ systems, including the intestines and central nervous system. However, previous studies are mostly limited to qualitative analysis of lymphatic structural changes and quantification of intestinal collecting vessel contractile function. It is not clear whether decreased lymphatic function contributes to pathological conditions related to aging, nor how it affects the skin immune microenvironment. Further, the effects of aging on skin initial and collecting lymphatic vessels, dendritic cell (DC) migration, cutaneous lymphatic pumping, and VEGFR-3 signaling in lymphatic endothelial cells (LECs) have not been quantitatively analyzed. Here, using fluorescent immunohistochemistry and flow cytometry, we confirm that aging decreases skin initial and collecting lymphatic vessel density. Indocyanine green (ICG) lymphangiography and DC migration assays confirm that aging decreases both fluid pumping and cell migration via lymphatic vessels. At the cellular level, aging causes decreased VEGFR-3 signaling, leading to increased LEC apoptosis and senescence. Finally, we determined that aging causes decreased lymphatic production of chemokines and alters LEC expression of junctional and adhesion molecules. This in turn leads to increased peri-lymphatic inflammation and nitrosative stress that might contribute to aging pathology in a feed-forward manner. Taken together, our study, in addition to quantitatively corroborating previous findings, suggests diverse mechanisms that contribute to lymphatic dysfunction in aging that in turn exacerbate the pathology of aging in a feed-forward manner.

Project description:The lymphatic endothelium (LE) serves as a conduit for transport of immune cells and soluble antigens from peripheral tissues to draining lymph nodes (LNs), contributing to development of host immune responses and possibly dissemination of microbes. Lymphatic endothelial cells (LECs) are major constituents of the lymphatic endothelium. These specialized cells could play important roles in initiation of host innate immune responses through sensing of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including toll-like receptors (TLRs). LECs secrete pro-inflammatory cytokines and chemokines to create local inflammatory conditions for recruitment of naïve antigen presenting cells (APCs) such as dendritic cells (DCs) to sites of infection and/or vaccine administration. In this study, we examined the innate immune potential of primary LEC populations derived from multiple tissues of an animal model for human infectious diseases - the ferret. We generated a total of six primary LEC populations from lung, tracheal, and mesenteric LN tissues from three different ferrets. Standard RT-PCR characterization of these primary LECs showed that they varied in their expression of LEC markers. The ferret LECs were examined for their ability to respond to poly I:C (TLR3 and RIG-I ligand) and other known TLR ligands as measured by production of proinflammatory cytokine (IFNα, IL6, IL10, Mx1, and TNFα) and chemokine (CCL5, CCL20, and CXCL10) mRNAs using real time RT-PCR. Poly I:C exposure induced robust proinflammatory responses by all of the primary ferret LECs. Chemotaxis was performed to determine the functional activity of CCL20 produced by the primary lung LECs and showed that the LEC-derived CCL20 was abundant and functional. Taken together, our results continue to reveal the innate immune potential of primary LECs during pathogen-host interactions and expand our understanding of the roles LECs might play in health and disease in animal models.

Dataset Information

Structural and functional analysis of the newt lymphatic system.

Publications

Structural and functional analysis of the newt lymphatic system.

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